IND Enabling Studies for a Novel Mas Receptor Agonist for Treatment of Cognitive Impairment in Patients at Risk for Alzheimer's Disease Related Dementia

项目摘要 在拟定的早期NIA U 01 ADDP项目中，我们将：1）完成我们的先导化合物的剂量优化， 2)完成PK/PD检测，3）开始生产、配制以及毒理学和安全性分析 要求将我们的先导化合物推进到IND申请和针对血管风险患者的临床研究中 对认知障碍和痴呆（VCID）的贡献以及向阿尔茨海默病和相关疾病的转化 痴呆症（ADRD）。我们的愿景是成为一流的治疗，以减少炎症性疾病相关的 认知障碍和抑制痴呆症的发展，在患者的风险为VCID和ADRD。我们将 利用我们目前批准的FDA IND # 125320和正在进行的使用天然药物的试验的经验， Ang-（1-7）治疗心力衰竭（HF）或心脏病患者的认知障碍，以推进我们的研究。 第二代糖基化Ang-（1-7），以完成IND提交所需的全部监管毒理学， I期安全性研究。我们的综合亚利桑那大学和ProNeurogen团队的肽药用 化学家、神经科学家、药理学家和制药工业专家已经开发出一种新的方法， 利用G蛋白连接的Mas受体的抗炎和神经保护性质， 我们在Ang-（1-7）激动剂方面的丰富经验。在大脑中，Mas受体在神经元上表达， 小胶质细胞和血管内皮细胞和Mas的激活降低ROS和脑炎症，增加 脑循环通过增加内皮NO释放和抑制缺氧诱导因子-1 α 1，3，17。我们 研究团队已经开发、优化并完成了高通量的体外和体内筛选新的 具有突出的脑渗透性和增强的稳定性的合成的Ang-（1-7）糖肽衍生物 2,4,6,10,12.我们已经完成了对主要候选人的全面理化分析。随着目标的完成， 下文中，我们将获得向FDA提交新IND的方案和必要文件，以便开始临床试验 在患者中进行认知障碍试验，作为发生VCID或ADRD的风险。多样性补充将 重点关注母公司申请的特定目的，重点关注纳入绝经期女性。的 将由补充候选物直接解决的相关具体假设如下： 假说.糖基化的Ang 1-7肽（PNA 5）将显着提高Ang 1-7的生物利用度， 增加绝经期女性脑中PNA 5浓度，几乎没有或没有BBB破坏， 通过G蛋白连接的Mas受体的激活证明VCID认知障碍。 因此，为了解决特定假设，将执行以下特定目标： Aim Ia.确定最小有效剂量（MED）、最佳有效剂量（OED）和最佳剂量 天然Ang-（1-7）和PNA 5在绝经期女性中用于认知保护的频率。 阿姆湾评估和比较绝经期女性中天然Ang-（1-7）和PNA 5的ADME和PK。 艾姆岛绝经期女性中的靶标结合和生物标志物炎症测定。

PROJECT SUMMARY In the proposed early stage NIA U01 ADDP program, we will: 1) finalize dose-optimization of our lead compound, 2) complete PK/PD testing and, 3) begin manufacturing, formulation and the toxicological and safety analyses required to advance our lead compound to IND submission and clinical studies for patients at risk for Vascular Contributions to Cognitive Impairment and Dementia (VCID) and conversion to Alzheimer's Disease and Related Dementias (ADRD). Our vision is to be a first-in-class therapy to reduce inflammatory-disease related cognitive impairment and inhibit dementia development in patients at risk for VCID and ADRD. We will leverage our experience with our currently approved FDA IND # 125320 and ongoing trials for the use of native Ang-(1-7) treatment of cognitive impairment in patients with heart failure (HF) or cardiac disease to advance our 2nd-generation glycosylated Ang-(1-7), to complete full regulatory toxicology needed for IND submission and Phase I safety studies. Our comprehensive University of Arizona and ProNeurogen team of peptide medicinal chemists, neuroscientists, pharmacologists and drug industry specialists have developed a novel approach to take advantage of the anti-inflammatory and neuroprotective nature of the G-protein linked Mas receptor and our extensive experience with Ang-(1-7) agonists. Within the brain, the Mas receptor is expressed on neurons, microglia and vascular endothelial cells and activation of Mas decreases ROS and brain inflammation, increases cerebral circulation via increases in endothelial NO release and inhibits hypoxia-inducing factor-1alpha 1,3,17. Our research team has developed, optimized and completed high-throughput in vitro and in vivo screens of novel synthetic glycopeptide derivatives of Ang-(1-7) that have outstanding brain penetration and enhanced stability 2,4,6,10,12. We have completed full physiochemical profiling of our lead candidate. With the completion of the Aims below, we will obtain the protocols and necessary documentation to file a new IND with the FDA to begin clinical trials for cognitive impairment in patients as risk for developing VCID or ADRD. The diversity supplement will focus on Specific Aim of the parent application with a focus on the inclusion of menopausal females. The pertinent specific hypothesis that will be directly addressed by the supplement candidate is as follows: Hypothesis. The glycosylated Ang 1-7 peptide (PNA5) will significantly improve bio-availability of Ang 1-7 and increase PNA5 concentration in the brain, in menopausal females, with little to no BBB disruption, who demonstrate VCID cognitive impairment via activation of the G-protein linked Mas receptor. Accordingly, to address the specific hypothesis, the following Specific Aims will be executed: Aim Ia. Identify Minimal Effective Dose (MED), Optimal Effective Dose (OED) and Optimal Dose Frequency for native Ang-(1-7) and PNA5 for cognitive protection in menopausal females. Aim Ib. Assess and compare ADME and PK for native Ang-(1-7) and PNA5 in menopausal females. Aim Ic. Target Engagement and Biomarker Inflammatory Assay in menopausal females.